COLLOIDAL IRON-OXIDE NANOBEACONS FOR THERANOSTIC USE IN ATHEROSCLEROSIS

用于动脉粥样硬化治疗的胶体氧化铁纳米信标

• 批准号: 7736580
• 负责人: Gregory M Lanza
• 金额: $ 70.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736580
• 关键词: Abate; Address; Angiogenesis Inhibitors; Animal Model; Arterial Fatty Streak; Atherosclerosis; Avidity; Back; Biodistribution; Biological Markers; Blood; Blood Vessels; Canis familiaris; Cardiovascular system; Carotid Endarterectomy; Chemicals; Clinic; Coagulation Process; Contrast Media; Coupled; Development; Disease; Disease Progression; Drug Delivery Systems; Drug Kinetics; Early Diagnosis; Effectiveness; Embolism; Encapsulated; Event; Fibrin; Fibrosis; Fluorocarbons; Gadolinium; Generations; Hemorrhage; Hour; Human; Image; In Vitro; Individual; Integrins; Kidney Diseases; Ligands; Magnetic Resonance Imaging; Magnetism; Manganese; Medical; Medicine; Membrane; Metabolism; Modeling; Monoclonal Antibodies; Morphologic artifacts; Nanotechnology; Natural History; Omniscan; Oryctolagus cuniculus; Outcome; Parents; Pathology; Pathway interactions; Patients; Pattern; Peptides; Phage Display; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Predisposition; Process; Property; Recording of previous events; Reporting; Risk; Rupture; Site; Specimen; Surface; Suspension substance; Suspensions; Symptoms; Synthesis Chemistry; Technology; Therapeutic; Thrombus; Time; Translating; angiogenesis; antiangiogenesis therapy; base; burden of illness; clinically relevant; crosslink; design; dosage; high risk; improved; in vivo; indexing; iron oxide; liver transplantation; macrophage; molecular imaging; nanocolloid; nanoemulsion; nanomedicine; nanoparticle; neovascular; neovasculature; novel; pre-clinical; prevent; response; safety study; success; surfactant; uptake

Nanomedicine approaches to atherosclerotic disease could have significant impact on the practice and outcomes of cardiovascular medicine. With recent concerns about the use of gadolinium and its relationship to Nephrogenic Systemic Fibrosis (NSF), alternative theranostic approaches need to be developed. The most likely first candidate are iron oxide nanoparticles, which have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties. Unfortunately, these agents typically result in a negative contrast effects that can only be imaged 24 or more hours after due to persistent blood pool interference. Although recent imaging sequence and processing advances can convert these dark contrast voxels into bright ones, the delay in imaging, the prominent blooming effects of the magnetic susceptibility, and the issue of nonspecific uptake of USPIOs by macrophages within the vascular wall at the time imaging can be performed are persistent problems. We have developed a novel, colloidal iron oxide nanoparticle platform, CION, which encapsulates iron oxide within a hydrophobic matrix and decreases T2 effects more than T1. These favorable T1w contrast attributes of CION are dependent on the synthesis chemistry, including the phase, magnetic susceptibility, and concentration of iron oxide in the matrix as well as the use of modest cross-linking in the outer surfactant membrane. CION novel beneficial properties include: 1) T1w molecular imaging without the typical dipole induced bloom artifacts, 2) in vivo molecular imaging after 1 hour (vs. 24) without blood pool interference, 3) theranostic capability to deliver an antiangiogenic drug and 4) constrained blood pool distribution to increase specific targeting of intravascular pathology, such as fibrin within ruptured plaques or integrins expressed by the neovasculature. In this modified proposal, we will develop CION technology and or a manganese nanoemulsion alternative (in back-up), with two broad, clinically relevant specific aims. Synthesize, characterize, and demonstrate in vivo (physical, chemical, magnetic, and pharmaceutical) of ligand-targeted non-gadolinium nanoplatform for T1W MR imaging of thrombus and of atherosclerotic neovasculature. Demonstrate image-guided drug delivery of antiangiogenic therapy potential with ligand-targeted non-gadolinium nanoplatform in vivo.

动脉粥样硬化疾病的纳米医学方法可能会对心血管医学的实践和结果产生重大影响。由于最近担心使用Gadolinium及其与肾脏发质全身纤维化（NSF）的关系，需要开发出替代性溶液方法。最有可能的第一个候选是氧化铁纳米颗粒，这些纳米颗粒已广泛用于基于高敏感的T2*成像性能的非靶向和靶向成像应用。不幸的是，这些药物通常会导致负造影剂效应，由于持续的血液池干扰，只能在24或更长时间内成像。尽管最近的成像序列和处理的进步可以将这些深色对比体素转换为明亮的体素，但成像的延迟，磁化敏感性的显着盛开效应以及在当时成像时血管壁中巨噬细胞对USPIO的非特异性吸收问题可能是持续的问题。我们已经开发了一种新型的氧化铁纳米颗粒平台Cion，该平台将氧化铁包裹在疏水基质中，而T2效应比T1降低了。 CION的这些有利的T1W对比属性取决于合成化学，包括矩阵中氧化铁的相，磁敏感性和氧化铁浓度，以及在外表面活性剂膜中使用适度的交联。 CION新颖的有益特性包括： 1）T1W分子成像，没有典型的偶极子诱导的花朵伪像， 2）1小时后的体内分子成像（vs. 24）无血池干扰， 3）提供抗血管生成药物的疗法能力和 4）受限的血液池分布增加了血管内病理学的特异性靶向，例如破裂的斑块中的纤维蛋白或新近神经系统表达的整联蛋白。 在这项修改后的建议中，我们将开发CION技术和 /或锰纳米乳液替代方案（在后备中），并具有两个广泛的临床相关特定目的。 符合性的非核心纳米平台的体内（物理，化学，磁性和药物）的合成，表征和证明，用于血栓和动脉粥样硬化新生血管造成T1W MR成像。 证明了抗血管生成疗法的图像引导的药物递送在体内靶向配体的非纳米平台的抗血管生成疗法。